Mycobacterium tuberculosis (Mtb) infects over one billion people, resulting in 9 million cases of tuberculosis (TB) annually, and over 1 million deaths each year. The majority of Mtb-infected individuals are unable to eliminate the pathogen, but can control it and establish latent TB. One of the biggest risk factors for developing active TB is co-infection with human immunodeficiency virus (HIV). Recent studies have shown that the majority of co-infected individuals are infected with HIV first and subsequently co-infected with Mtb. T cell responses play a critical role in containing Mtb, so it is not surprising that immunodeficient HIV+ individuals are likely to develop active TB. Notably, HIV+ persons on HAART or who have high CD4 counts are still more likely to develop active TB than someone who is HIV-nave. Clearly, factors besides simply CD4 depletion in blood must contribute to the increased likelihood of active TB in co-infected individuals. Nonhuman primates infected with Mtb recapitulate all aspects of human TB, and those infected with simian immunodeficiency virus (SIV) display symptoms similar to HIV/AIDS. Using SIV+ Mauritian cynomolgus macaques (MCM), we will identify the mechanism by which pre-existing SIV infection interferes with host control over an Mtb infection. We hypothesize that SIV impairs the early Th1 and Th17 cytokine response by T cells in granulomas, which prevents control of Mtb replication. To test this hypothesis, we will track epitope-specific T cells with tetrameric molecules in the blood and granuloma lesions of MCM co-infected with SIV and Mtb. We will also use state-of-the-art PET/CT imaging to characterize the early formation of granulomas in lung tissue of SIV+ animals after Mtb co-infection. Lastly, we will determine if a novel subunit TB vaccine can boost cellular immune responses in SIV+ animals and re- establish the ability to control a subsequent Mtb challenge. This proposal brings together two investigators with complimentary expertise to provide new insights into the events that impair control of Mtb infection in the setting of pre-existing HIV infection. Novel studies in a highly relevant animal model will lead to an understanding of the critical events in early Mtb infection that prevent establishment of latent TB and will evaluate the potential of boosting immunity to Mtb in SIV+ animals.